SAN DIEGO (FRONTLINE MEDICAL NEWS) – Metadoxine extended release missed its primary endpoint in a phase III trial of adults with attention-deficit/hyperactivity disorder, Dr. Lenard A. Adler reported at the annual meeting of the American Academy of Child and Adolescent Psychiatry.
After 6 weeks of treatment, patients’ scores on the Conners’ Adult ADHD Investigator Rating Scale with adult prompts (CAARS-Inv) had dropped a mean of 12 points from baseline, compared with a 9.9-point decrease for the placebo group (P = .136), said Dr. Adler, a professor of psychiatry at NYU Langone Medical Center in New York.
The “nonsignificant positive trend” could be attributable in part to a “larger placebo effect than previously reported,” Dr. Adler said. The only significant result for the primary outcome measure came from a post hoc, modified intention-to-treat analysis that excluded entry criteria violations and patients with measures at least 3 standard deviations outside the mean, he added. Excluding those patients led to a 2.92 least-squares mean difference between the treatment and placebo groups, for a P value of .038, he reported.
Metadoxine is an ion-pair salt of vitamin B6 and 2-pyrrolidone-5-carboxylate. Since the 1980s, an immediate-release form of the drug has been available in certain countries for treating alcohol intoxication and alcoholic liver disease. Metadoxine has gamma-aminobutyric acid (GABAB) agonist-like activity and 5-hydroxytryptamine (5-HT2B) antagonist activity, but had little effect on dopamine, norepinephrine, or serotonin in studies of rats, Dr. Adler noted.
In a prior phase IIb, 6-week, double-blind study of 120 adults with ADHD, patients randomized to metadoxine 1,400 mg once daily had a drop in CAARS-Inv scores compared with the placebo group after 2 weeks of treatment (P < .05), Dr. Adler said. A subgroup analysis showed that the significant effect was confined to the 49 patients with the predominantly inattentive (PI) form of ADHD, he added (mean decrease, 13.4 points for metadoxine vs. 6.6 points for placebo; P < .05).
In a smaller phase IIb study of 36 Israeli patients with PI-ADHD, 1,400-mg extended-release metadoxine also was linked to a 2-point improvement in the Test of Variables of Attention ( TOVA ), compared with placebo (P = .009), Dr. Adler reported. A lower dose of 700 mg of the drug did not outperform placebo (difference in TOVA scores, 0.1 point; P = .899), he said.
The phase III trial included 300 adults with ADHD who were treated at 20 sites in the United States and Israel, Dr. Adler said. Patients were aged 18-55 years and had baseline CAARS-Inv scores of at least 22 (mean, 38, ranging up to 53-54). Based on the phase IIb trial results, researchers randomized the patients so that one-third of each group had patients with PI-ADHD, he added.
The drug was well tolerated, with no serious adverse events, Dr. Adler said. A phase II trial of metadoxine extended release in adolescents is ongoing, as is a phase IIb study of the drug in adults and adolescents with fragile X syndrome, he said.
Alcobra makes metadoxine and funded the study. Dr. Adler reported receiving honoraria for consulting with Alcobra and for serving on its advisory board.